Elevation of blood flow velocity in the large cerebral vessels is known to be of substantial pathophysiologic and prognostic significance in sickle-cell disease (SCD). Its precise cause is not established, but the two obvious proximal mechanisms are obstructive vascular stenosis and hemodynamic dilatation. Here we revisit this distinction by analyzing cerebrovascular reserve capacity. Forty-two patients with SCD underwent measurements of global cerebral blood flow in grey matter by the 133Xe inhalation method during normocapnia and hypercapnia to quantify cerebrovascular reactivity. Cerebral blood flow was significantly higher in SCD patients (120+/-31 ml/100 g/min) than in controls (76+/-20 ml/100 g/min). Reactivity was significantly lower in SCD patients (1.06+/-1.92 versus 2.16+/-1.15%/mm Hg). Stepwise multiple regressions within the SCD sample determined that normocapnic cerebral blood flow was largely predicted by hematocrit (r=-0.59; P<0.0001), whereas hypercapnic reactivity was only predicted by normocapnic flow across all subjects (r=-0.52; P<0.0001). None of the controls, but 24% of the SCD patients showed 'steal' (negative reactivity, chi2=6.05; P<0.02). This impairment of vasodilatory capacity, occurring at perfusion levels above 150 ml/100 g/min, may reflect intrinsic limitations of the human cerebrovascular system and can explain both the elevated blood flow velocities and the high risk of stroke observed in such patients.